ObjectivesThe aim of this 12-week Phase IIb study was to assess the efficacy and safety of olokizumab (OKZ), a humanised anti-IL6 monoclonal antibody, in patients with rheumatoid arthritis (RA) with moderate-to-severe disease activity who had previously failed tumour necrosis factor (TNF) inhibitor therapy. The dose-exposure-response relationship for OKZ was also investigated.MethodsPatients were randomised to one of nine treatment arms receiving placebo (PBO) or OKZ (60, 120 or 240 mg) every 4 weeks (Q4W) or every 2 weeks (Q2W), or 8 mg/kg tocilizumab (TCZ) Q4W. The primary endpoint was change from baseline in DAS28(C-reactive protein, CRP) at Week 12. Secondary efficacy endpoints were American College of Rheumatology 20 (ACR20), ACR50 and ACR70 response rates at Week 12. Exploratory analyses included comparisons of OKZ efficacy with TCZ.ResultsAcross 221 randomised patients, OKZ treatment produced significantly greater reductions in DAS28(CRP) from baseline levels at Week 12, compared to PBO (p<0.001), at all the OKZ doses tested (60 mg OKZ p=0.0001, 120 and 240 mg OKZ p<0.0001). Additionally, ACR20 and ACR50 responses were numerically higher for OKZ than PBO (ACR20: PBO=17.1–29.9%, OKZ=32.5–60.7%; ACR50: PBO=1.3–4.9%, OKZ=11.5–33.2%). OKZ treatment, at several doses, demonstrated similar efficacy to TCZ across multiple endpoints. Most adverse events were mild or moderate and comparable between OKZ and TCZ treatment groups. Pharmacokinetic/pharmacodynamic modelling demonstrated a shallow dose/exposure response relationship in terms of percentage of patients with DAS28(CRP) <2.6.ConclusionsOKZ produced significantly greater reductions in DAS28(CRP) from baseline at Week 12 compared with PBO. Reported AEs were consistent with the safety profile expected of this class of drug, with no new safety signals identified.Trial register number:NCT01242488.

We previously postulated that active Na transport by the esophageal stratified squamous epithelium is important for maintenance of its barrier function. To investigate this further we studied the effects of HCl on the in vivo esophageal potential difference (PD), on in vitro Na transport, and on esophageal Na-K-ATPase activity. In vivo esophageal perfusion with low concentrations of HCl (20 or 40 mM) increased the PD and a high concentration (120 mM) decreased it. An intermediate concentration (80 mM) caused a biphasic response with an initial increase in PD followed by a progressive decrease in PD. In vitro transport studies were performed to explain the increased in vivo PD. In the presence of luminal H+ the increased PD resulted from H+ diffusion from lumen to blood, whereas after H+ exposure the increased PD was due largely to increased net Na transport from lumen to blood through an amiloride-sensitive mechanism. In tissues with prolonged exposure to 80 mM HCl (PD decreased 80-100%), Na-K-ATPase activity was significantly inhibited (1.94 +/- 0.32 vs. 5.12 +/- 0.73 mumol P X mg prot-1 X h-1). Thus, HCl initially increases the in vivo esophageal PD by H+ transport from lumen to blood, a process replaced by stimulated net Na transport when H+ is replaced by Na. Prolonged acid exposure ultimately decreases Na exit from cells by inhibiting Na-K-ATPase activity. This sequence suggests that alterations in Na transport could result in cell edema and necrosis via loss of cell volume regulation.

To assess Na-K-ATPase inhibiton and prostaglandin synthesis stimulation as the mechanism of the secretory (cathartic) action of phenolphthalein in the primate, we investigated water and electrolyte transport and Na-K-ATPase levels in monkey intestine. Both jejunum and colon were studied with in vivo perfusion and in vitro Ussing chamber techniques. Water, Na, and Cl absorption was inhibited or secretion was induced by phenolphthalein (10(-3) M) in the jejunum and colon when the drug was present in the mucosal bathing (perfusion) solution. Serosal addition of phenolphthalein (10(-4) or 10(-3) M) induced Na and anion absorption in the jejunum but not in the colon. Phenolphthalein inhibited Na-K-ATPase activity in the test tube, but assays of intestine previously perfused or bathed in the drug showed no inhibiton. Indomethacin, in doses sufficient to inhibit prostaglandin synthesis in the intestine, inhibited the secretion induced by phenolphthalein in the jejunum but not in the colon. These inconsistencies cast doubt on the role of Na-K-ATPase inhibition or the role of prostaglandin synthesis stimulation in the mechanism of action of phenolphthalein.

Modest differences in the clearance of the 5HT3 antagonist, ondansetron, among different age groups were detected in two groups of healthy elderly volunteers, one group aged 61 to 74 years ("elderly") and the other 75 to 82 ("aged") years, in addition to young healthy subjects. Both a single 0.15 mg/kg intravenous dose and a single 8 mg oral dose were administered according to a randomized crossover design with a minimum 3-day washout period between treatments. Mean plasma clearance decreased (young, 0.349 L/hr/kg; elderly, 0.279 L/hr/kg; aged, 0.214 L/hr/kg; p less than 0.05) with increasing age. Volume of distribution at steady state was unaffected by age (young, 1.81 L/kg; elderly, 1.94 L/kg; aged, 1.71 L/kg), resulting in increases in mean plasma half-life (young, 3.4 hours; elderly, 4.5 hours; aged, 5.4 hours) and mean absolute bioavailability (young, 57%; elderly, 61%; aged, 69%) with increasing age. Female subjects cleared ondansetron more slowly than males (p less than 0.05), resulting in higher absolute bioavailability. Ondansetron was well tolerated by all age groups with no increase in the number of adverse events observed in older volunteers.

Oral ondansetron is an effective therapy for the prevention of emesis induced by TBI.

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